1. Field of the Invention
The present invention relates to an improved method for the synthesis of analogs of desferrioxamine B and homologs thereof.
2. Description of the Prior Art
The microbial iron chelator, siderophore, desferrioxamine B [N'-[5-[4-[[5-acetylhydroxyamino)pentyl]amino-1,4-dioxobutyl]hydroxyamino] pentyl]-N-(5-aminopentyl)-N-hydroxybutane diamide] was isolated from Streptomyces pilosus and characterized by Bickel ["Metabolic products of actinomycetes. Ferrioxamine B," Helv. Chim. Acta., Vol. 43, pp. 2129-2138] in 1960. It is a linear trihydroxamate ligand which forms a very stable hexacoordinate, octahedral [Modell et al, "The Clinical Approach to Thalassaemia," Grune and Stratton, London, pp. 217-241 (1984)] complex with Fe (III), K.sub.f =1.times.10.sup.30 M.sup.-1. The ligand employs its three bidentate hydroxamate units in chelating metal ions.
Although desferrioxamine B will bind a number of different +3 cations, e.g., Al (III), Ga (III), Cr (III), it exhibits a high specificity for Fe (III), and is utilized by Streptomyces pilosus for the acquisition of iron from the environment. Because of the metal selectivity and low toxicity of the ligand, it has been employed in the treatment of several iron overload diseases, e.g., thalassaemia ["Development of Iron Chelators for Clinical Use," Martell et al, eds., Elsevier, North Holland; N.Y. (1981)]. However, desferrioxamine B does not offer a completely satisfactory solution to the iron overload problem. The drug is cleared by the kidneys and has a very short half-life in the body; thus, the patient must be maintained on constant infusion therapy. It is not orally effective. Because of these shortcomings, investigators have explored the potential of other ligands as therapeutic iron chelators. To date, these investigations have not included modification of the desferrioxamine molecule simply because of the lack of high yield of facile approaches to the synthesis of the molecule.
Desferrioxamine B was first synthesized in 1962 by Prelog et al ["Metabolic products of actinomycetes. Synthesis of Ferrioxamines B and D," Helv. Chim. Acta., Vol 45, pp. 631-637 (1962)]. However, because of the number of steps in the synthesis and the low yield of the sequence, the method does not enable the production of large quantities of the chelator or its analogs. A retro-synthetic analysis of the ligand reveals that the desferrioxamine molecule is made up of two fundamental units: 1-amino-5-(N-hydroxyamino)pentane and succinic acid. The key to its synthesis is the production of this amino-hydroxyaminopentane unit and its condensation with succinic acid. Prelog approached this problem beginning with the starting material 1-amino-5-nitropentane, an amine which was accessible in only 46% yield [Bickel et al, "Metabolic products of actinomycetes. Isolation and synthesis of 1-amino-5-(hydroxyamino)pentane, an essential hydrolysis product of ferrioxamine and ferrimycin," Helv. Chim, Acta., Vol. 43, pp. 901-904 (1960)]. This compound was next N-carbobenzoxylated and the terminal nitro group reduced to the corresponding hydroxyamino group. This key intermediate was condensed with succinic acid followed by a series of other dicyclohexylcarbodiimide catalyzed acylations along with several reductions to produce desferrioxamine B. The overall yield of this eleven-step sequence was 6%.
Although desferrioxamine is currently the drug of choice in the treatment of thalassemia, it nevertheless suffers from several shortcomings. The drug is not orally effective and, therefore, must be administered by infusion. Furthermore, because of its short half-life in the body, patients must be maintained on continuous infusion therapy for extended periods of time. As a result, patient compliance is the principal difficulty associated with the drug. In order to overcome these problems, investigators have explored the therapeutic potential of alternative iron chelators over the years, albeit with somewhat limited success. It was an object of the search that led to the present invention to identify the minimal structural requirements of the desferrioxamine platform which are still compatible with the molecule's iron-clearing properties. Once having identified such a pharmacophore, it was converted to pharmacophores which are more readily absorbed in the gastrointestinal tract, specifically, hexacoordinate DFO analogs in which the amides are removed and the molecules are shortened.
Bergeron et al ["An Efficient Total Synthesis of Desferrioxamine B," J. Org. Chem., vol 53, pp 3131-3134 (1988)] reported a total synthesis of desferrioxamine B (DFO) in which the construction moved from the N-acetyl to the primary amine end of the molecule.
U.S. Pat. No. 4,987,253 and U.S. patent application Ser. No. 07/784,949 filed Oct. 30, 1991, each disclose novel syntheses for desferrioxamine B and analogs and homologs thereof.
It is an object of the present invention to provide novel, improved, high yield methods for the production of analogs of desferrioxamine B and homologs thereof.